Investigating mechanisms of chemoresistance in triple-negative breast cancer

研究三阴性乳腺癌的化疗耐药机制

• 批准号: 10747715
• 负责人: Madeleine Julie Oudin
• 金额: $ 4.89万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-11 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747715
• 关键词: Adipocytes; Adjuvant Chemotherapy; Affect; Aftercare; Automobile Driving; Breast Cancer Cell; Breast Cancer Patient; Cancer Burden; Caspase; Cathepsins B; Cell secretion; Cessation of life; Chemoresistance; Clinical; Collagen; Collagen Type IV; Crosslinker; Data; Development; Drug resistance; Endothelial Cells; Environment; Excision; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Gene Expression Profile; Glycoproteins; Goals; Human; In Vitro; Individual; Invaded; Laminin; Macrophage; Malignant Neoplasms; Mammary Neoplasms; Metastasis Induction; Metastatic/Recurrent; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Paclitaxel; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Play; Population; Process; Property; Proteins; Proteoglycan; Recurrence; Relapse; Research; Residual Cancers; Resistance; Role; Sampling; Signal Transduction; Structural Protein; Structure; Testing; Therapeutic; Tissues; Tumor Tissue; Up-Regulation; cell motility; cell type; chemotherapy; improved; in vivo; insight; malignant breast neoplasm; neoplastic cell; novel; prevent; response; standard of care; therapy outcome; three-dimensional modeling; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary Chemotherapy remains the standard of care for patients with triple-negative breast cancer (TNBC), which affects 20% of patients with breast cancer. However, 50% of patients with localized TNBC treated with neoadjuvant chemotherapy display residual cancer burden after treatment and up to 25% of patients who receive this treatment will suffer metastatic recurrence within five years. The poor association between chemotherapy and patient outcome emphasizes two major problems for TNBC patients: chemoresistance, where tumor cells within the local environment are protected and do not die in response to chemotherapy, and chemotherapy-induced metastasis, where chemotherapy-induced changes in tumor intrinsic properties and the tumor microenvironment drive invasion which leads to recurrence. Previous studies have demonstrated that cell migration and extracellular matrix (ECM) remodeling are associated with chemoresistant TNBC. The goal of this proposal is to understand the mechanisms by which the ECM contributes to chemoresistance and chemotherapy-induced metastasis in TNBC. We provide preliminary data that individual proteins upregulated in TNBC tumors drive resistance to chemotherapy drug Paclitaxel and that expression of Cathepsin B (CTSB), a protease which degrades these ECM proteins into small fragments, protects against the development of chemoresistance. We will dissect the mechanism by which the protease CTSB and the ECM proteins it degrades influence response to Paclitaxel in TNBC and whether these fragments can be used to track and target chemoresistance in vivo. We have also found that chemotherapy treatment leads to changes in the ECM composition of mammary tumors. Specifically, Paclitaxel treatment leads to an increased abundance of Collagen IV, an ECM protein which promote invasion and metastasis in TNBC. Our goal is to determine the cell types that secrete ECM proteins such as Collagen IV after chemotherapy treatment, determine the contribution of these ECM proteins to chemotherapy-induced metastasis, and whether these pathways can be targeted to prevent the development of recurrence. Upon successful completion of the proposed research, our contribution is expected to be an understanding of how ECM proteins upregulated in TNBC tumors contribute to chemoresistance and how chemotherapy alters the ECM to promote recurrence and metastatic dissemination. These contributions will be significant because all TNBC patients receive chemotherapy and metastatic recurrence is a current unmet clinical need. Results from these studies will provide novel conceptual insights on mechanisms of chemoresistance and chemotherapy-induced metastasis and will allow us to develop new strategies to track, predict and overcome chemoresistance in TNBC.

项目摘要 化疗仍然是三阴性乳腺癌（TNBC）患者的标准治疗， 影响了20%的乳腺癌患者然而，50%的局部TNBC患者接受 新辅助化疗显示治疗后残留的癌症负荷，高达25%的患者 接受这种治疗将在五年内出现转移性复发。之间的不良关联 化疗和患者结果强调了TNBC患者的两个主要问题：化疗抗性， 其中局部环境中的肿瘤细胞受到保护并且不会响应于化疗而死亡，以及 化疗诱导的转移，其中化疗诱导的肿瘤内在性质的变化和肿瘤细胞的增殖， 肿瘤微环境驱动侵袭，导致复发。先前的研究表明， 细胞迁移和细胞外基质（ECM）重塑与化学抗性TNBC相关。目标 这项建议的目的是了解ECM导致化疗耐药性的机制， 在TNBC中化疗诱导的转移。 我们提供的初步数据表明，在TNBC肿瘤中上调的个别蛋白质驱动了对TNBC的耐药性。 化疗药物紫杉醇和组织蛋白酶B（CTSB）表达，CTSB是一种降解这些蛋白酶的蛋白酶 ECM蛋白分裂成小片段，防止化学抗性的发展。我们将解剖 蛋白酶CTSB及其降解的ECM蛋白影响对Paclitaxin反应的机制 TNBC以及这些片段是否可用于跟踪和靶向体内化学抗性。我们还 发现化疗治疗导致乳腺肿瘤细胞外基质成分的变化。 具体而言，紫杉醇治疗导致IV型胶原蛋白丰度增加，IV型胶原蛋白是一种ECM蛋白， 促进TNBC的侵袭和转移。我们的目标是确定分泌ECM蛋白的细胞类型 如IV型胶原蛋白，确定这些ECM蛋白对 化疗诱导的转移，以及是否可以靶向这些途径以防止其发展 的复发。 在成功完成拟议的研究后，我们的贡献预计将是了解 ECM蛋白在TNBC肿瘤中的上调如何导致化疗耐药性以及化疗如何改变 ECM促进复发和转移性播散。这些贡献将是巨大的，因为 所有TNBC患者都接受化疗，并且转移复发是目前未满足的临床需求。结果 这些研究将为化学抗性机制提供新的概念性见解， 化疗诱导的转移，并将使我们能够开发新的策略来跟踪，预测和克服 TNBC中的化学抗性。